Benzodiazepine overdose

Source: Wikipedia, the free encyclopedia.
Benzodiazepine overdose
Other namesBenzodiazepine poisoning
US yearly overdose deaths involving benzodiazepines.[1]
SpecialtyToxicology, emergency medicine
Benzodiazepines
Chemical structure diagram of a benzene ring fused to a diazepine ring. Another benzene ring is attached to the bottom of the diazepine ring via a single line. Attached to the first benzene ring is a side chain labeled R7; to the second, a side chain labeled R2'; and attached to the diazepine ring, two side chains labeled R1 and R2.
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.

Benzodiazepine overdose (BZD OD) describes the ingestion of one of the drugs in the

respiratory depression. Supportive care is the mainstay of treatment of benzodiazepine overdose. There is an antidote, flumazenil, but its use is controversial.[2]

Deaths from single-drug benzodiazepine overdoses occur infrequently,

tricyclic antidepressants [citation needed] are particularly dangerous, and may lead to severe complications such as coma or death. In 2013, benzodiazepines were involved in 31% of the estimated 22,767 deaths from prescription drug overdose in the United States.[5] The US Food and Drug Administration (FDA) has subsequently issued a black box warning regarding concurrent use of benzodiazepines and opioids.[6] Benzodiazepines are one of the most highly prescribed classes of drugs,[7] and they are commonly used in self-poisoning.[8][9] Over 10 years in the United Kingdom, 1512 fatal poisonings have been attributed to benzodiazepines with or without alcohol.[10] Temazepam was shown to be more toxic than the majority of benzodiazepines. An Australian (1995) study found oxazepam less toxic and less sedative, and temazepam more toxic and more sedative, than most benzodiazepines in overdose.[11]

Signs and symptoms

Following an acute overdose of a benzodiazepine the onset of symptoms is typically rapid with most developing symptoms within 4 hours.[12] Patients initially present with mild to moderate impairment of central nervous system function. Initial signs and symptoms include intoxication, somnolence, diplopia, impaired balance, impaired motor function, anterograde amnesia, ataxia, and slurred speech. Most patients with pure benzodiazepine overdose will usually only exhibit these mild CNS symptoms.[12][13] Paradoxical reactions such as anxiety, delirium, combativeness, hallucinations, and aggression can also occur following benzodiazepine overdose.[14] Gastrointestinal symptoms such as nausea and vomiting have also been occasionally reported.[13]

Cases of severe overdose have been reported and symptoms displayed might include prolonged deep coma or deep cyclic coma,

drug misuse in conjunction with other CNS depressants such as opioids or alcohol.[19][20][21][22] The duration of symptoms following overdose is usually between 12 and 36 hours in the majority of cases.[13] The majority of drug-related deaths involve misuse of heroin or other opioids in combination with benzodiazepines or other CNS depressant drugs. In most cases of fatal overdose it is likely that lack of opioid tolerance combined with the depressant effects of benzodiazepines is the cause of death.[23]

The symptoms of an

sleepiness, agitation and ataxia occur much more frequently and severely in children. Hypotonia may also occur in severe cases.[24]

Toxicity

The top line represents the number of benzodiazepine deaths that also involved opioids in the US. The bottom line represents benzodiazepine deaths that did not involve opioids.[1]

tricyclic antidepressants, or sedating antipsychotics, anticonvulsants, or antihistamines are particularly dangerous.[26] Additionally, emergency department visits involving benzodiazepines compared to other sedative-hypnotics have much higher odds of hospitalization, patient transfer, or death.[27] In the case of alcohol and barbiturates, not only do they have an additive effect but they also increase the binding affinity of benzodiazepines to the benzodiazepine binding site, which results in a very significant potentiation of the CNS and respiratory depressant effects.[28][29][30][31][32] In addition, the elderly and those with chronic illnesses are much more vulnerable to lethal overdose with benzodiazepines. Fatal overdoses can occur at relatively low doses in these individuals.[13][33][34][35]

Comparability

The various benzodiazepines differ in their toxicity since they produce varying levels of sedation in overdose. A 1993 British study of deaths during the 1980s found flurazepam and temazepam more frequently involved in drug-related deaths, causing more deaths per million prescriptions than other benzodiazepines. Flurazepam, now rarely prescribed in the United Kingdom and Australia, had the highest fatal toxicity index of any benzodiazepine (15.0), followed by temazepam (11.9), versus benzodiazepines overall (5.9), taken with or without alcohol.[36] An Australian (1995) study found oxazepam less toxic and less sedative, and temazepam more toxic and more sedative, than most benzodiazepines in overdose.[11] An Australian study (2004) of overdose admissions between 1987 and 2002 found alprazolam, which happens to be the most prescribed benzodiazepine in Australia and the United States, to be more toxic than diazepam and the other three benzodiazepines which it was compared to (alprazolam, diazepam, oxazepam, chlordiazepoxide, and clonazepam). They also cited a review of the Annual Reports of the American Association of Poison Control Centers National Data Collection System, which showed alprazolam was involved in 34 fatal deliberate self-poisonings over 10 years (1992–2001), compared with 30 fatal deliberate self-poisonings involving diazepam.[37] In a New Zealand study (2003) of 200 deaths, Zopiclone, a benzodiazepine receptor agonist, had similar, although less overdose potential compared to temazepam, which is the most toxic benzodiazepine.[38]

Pathophysiology

Benzodiazepines bind to a specific benzodiazepine receptor, thereby enhancing the effect of the neurotransmitter

evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. Toxic overdoses of benzodiazepines therefore cause prolonged CCT and IPLs.[39][40][41]

Diagnosis

The diagnosis of benzodiazepine overdose may be difficult, but is usually made based on the clinical presentation of the patient along with a history of overdose.

mass spectrometer, and radioimmunoassay.[13] Blood benzodiazepine concentrations, however, do not appear to be related to any toxicological effect or predictive of clinical outcome. Blood concentrations are, therefore, used mainly to confirm the diagnosis rather than being useful for the clinical management of the patient.[13][43]

Treatment

Flumazenil is a benzodiazepine antagonist that can reverse the effects of benzodiazepines, although its use following benzodiazepine overdose is controversial.

Medical observation and supportive care are the mainstay of treatment of benzodiazepine overdose.

lipid solubility.[45][46]

Supportive measures

Supportive measures include observation of

blood flow and heart rate.[13]

Flumazenil

ECG, anticholinergic signs, or a history of seizures.[49] Due to these contraindications and the possibility of it causing severe adverse effects including seizures, adverse cardiac effects, and death,[50][51] in the majority of cases there is no indication for the use of flumazenil in the management of benzodiazepine overdose as the risks in general outweigh any potential benefit of administration.[2][45] It also has no role in the management of unknown overdoses.[8][48] In addition, if full airway protection has been achieved, a good outcome is expected, and therefore flumazenil administration is unlikely to be required.[52]

Flumazenil is very effective at reversing the

respiratory depression.[48] One study found that only 10% of the patient population presenting with a benzodiazepine overdose are suitable candidates for flumazenil.[48] In this select population who are naive to and overdose solely on a benzodiazepine, it can be considered.[53] Due to its short half life, the duration of action of flumazenil is usually less than 1 hour, and multiple doses may be needed.[48] When flumazenil is indicated the risks can be reduced or avoided by slow dose titration of flumazenil.[47] Due to risks and its many contraindications, flumazenil should be administered only after discussion with a medical toxicologist.[53][54]

Epidemiology

In a Swedish (2003) study benzodiazepines were implicated in 39% of

death certificates. In 72% of the cases, benzodiazepines were the only drug consumed. Thus, many of deaths associated with benzodiazepine overdoses may not be a direct result of the toxic effects but either due to being combined with other drugs or used as a tool to kill oneself using a different method, e.g. drowning.[55]

In a Swedish retrospective study of deaths of 1987, in 159 of 1587 autopsy cases benzodiazepines were found. In 44 of these cases the cause of death was

drug addiction (N = 29) or alcoholism
(N = 10). In a comparison of suicides and natural deaths, the concentrations both of flunitrazepam and nitrazepam (sleeping medications) were significantly higher among the suicides. In four cases benzodiazepines were the sole cause of death.[56]

In Australia, a study of 16 deaths associated with toxic concentrations of benzodiazepines during the period of 5 years leading up to July 1994 found preexisting natural disease as a feature of 11 cases; 14 cases were suicides. Cases where other drugs, including ethanol, had contributed to the death were excluded. In the remaining five cases, death was caused solely by benzodiazepines. Nitrazepam and temazepam were the most prevalent drugs detected, followed by oxazepam and flunitrazepam.[57] A review of self poisonings of 12 months 1976 - 1977 in Auckland, New Zealand, found benzodiazepines implicated in 40% of the cases.[58] A 1993 British study found flurazepam and temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s. Flurazepam, now rarely prescribed in the United Kingdom and Australia, had the highest fatal toxicity index of any benzodiazepine (15.0) followed by Temazepam (11.9), versus 5.9 for benzodiazepines overall, taken with or without alcohol.[36]

Etizolam overdose deaths are rising - for instance, the National Records of Scotland report on drug-related deaths, implicated 548 deaths from 'street' Etizolam in 2018, almost double the number from 2017 (299) and only six years from the first recorded death (in 2012). The 548 deaths were 45% of all drug-related deaths in Scotland in 2018.[59]

References

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External links

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